Recirculating fluid filtration system

ABSTRACT

A fluid filtration system comprising a cross-flow filter is arranged to permit a first pump to recirculate part of the retentate of the filter to the inlet of the cross-flow filter and a second pump to return part of the permeate to the inlet of the cross-flow filter. A third pump is configured supply source fluid to the inlet of the filter. The flow path between the second pump and the cross-flow filter inlet may include an adsorption filter that may selectively remove contaminants, toxins, or pathogens in the permeate. A controller may control the first, second and third pumps to provide predetermined flow ratios among the fluid flow paths of the system in order to achieve a desired filtration level. This system may be applicable to the removal of harmful substances from blood, by first separating the plasma from the blood and then removing harmful substances from the plasma.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/161,898 filed May 23, 2016 (U.S. Publication No. US-2016-0263305-A1published Sep. 15, 2016), and to be issued on Mar. 31, 2020 as U.S. Pat.No. 10,603,425, entitled Recirculating Fluid Filtration System, which isa continuation of U.S. patent application Ser. No. 13/619,010, filedSep. 14, 2012, and entitled Recirculating Fluid Filtration System, nowU.S. Pat. No. 9,345,826, issued May 24, 2016, which claims the benefitof U.S. Provisional Patent Application Serial No. 61/535,135, filed Sep.15, 2011, and entitled Optimized Flow Loop for Fluid Filtration, whichis hereby incorporated by reference herein in its entirety.

TECHNICAL FIELD

The present invention relates to fluid filtration systems and methods.

BACKGROUND

In chemical engineering, biochemical engineering and proteinpurification, cross-flow filtration (also known as tangential flowfiltration) is a type of filtration where the majority of the feed flowtravels tangentially across the surface of the filter, rather thanthrough the filter. The permeate passes through the filter membrane orfilter media, while the retentate exits the filter body carrying theparticles too large to pass through the filter element. A range ofdifferent types of membranes are available that can be characterized bythe size of the particles and solutes that do not pass through themembrane. For example, in biological applications, plasma filters havemicrofiltration membranes that retain cells and other particles largerthan about 1 μm in the retentate, while allowing smaller particles(e.g., proteins) to pass through with the permeate. Also,ultrafilters—filters used to concentrate proteins—retain particleslarger than 10 kiloDalton. Nanofiltration generally involves filteringwith a pore size of about 0.001 micron, and can remove most organicmolecules, viruses, salts and divalent ions. Reverse osmosis—the mostrestrictive filtration with filters having a pore size of about 0.0001micron retains all particles and solutes including monovalent ions andmost minerals. The principal advantage of cross-flow filtration is thatthe filtered particles and solute are substantially washed away from thefilter surface during the filtration process, increasing the length oftime that a filter unit can be operational.

Flow systems typically control certain conditions such as, for example,pressure and flow rate, to achieve a preferred performance. The bloodpumping system of an extracorporeal blood purification system, forexample, is selected or configured so that the range of pressure andflow rate may be preferentially optimized for the characteristics of agiven patient access. However such systems may have particularcomponents (such as a plasma filter in the case of an extracorporealblood treatment system) whose optimal operating conditions differ fromthe preferred operating conditions of the system as a whole. In thefollowing description, the term solute is intended to broadly includemolecules, compounds or other substances dissolved in the fluid.Examples of solutes include but are not limited to salts or sugars. Inthe following description, the term particle is intended to broadlyinclude compounds, polymers, solid structures, biological cells, partsof cells, macro molecules, protein structures, etc. that are carried bythe fluid in a mixture or in suspension. Examples of particles includebut are not limited to whole blood cells, bacteria, viruses andproteins.

SUMMARY OF INVENTION

A fluid purification system comprises a cross-flow filter, a fluidconduit to re-circulate reject fluid or retentate from the filter, a1^(st) pump to drive the recirculation, a 2^(nd) pump to supply freshfluid to system and an exiting fluid conduit comprising a flow resistorto allow some of the retentate to exit the system. The cross-flow filterincludes an inlet port, a 1^(st) outlet port where retentate exits thefilter, and a 2^(nd) outlet port through which the filtered liquidpermeate exits. Liquid from the 1^(st) outlet port flows to the inletport via the recirculation loop. Flow through the recirculation loop andfilter is driven by the 1^(st) pump. Fresh fluid is supplied to therecirculation loop by a 2^(nd) pump. A portion of the retentate exitsthe recirculation loop via a fluid conduit that includes a flowresistor. The 2^(nd) pump supplies enough fluid flow to achieve adesired pressure in the filter given the flow resistances of the filtermembrane and flow resistor.

In an embodiment, a two-tiered pumping system may be used, comprisingtwo or more pumps. A feed booster pump supplies fluid from a fluidsource and delivers it to the feed fluid recirculation circuit. The pumpflow rate can be relatively small—enough to replace the filtered fluidoutput of the cross-flow filter and any additional fluid discharged fromthe recirculation circuit. The feed booster pump in combination with apressure relief device maintains the desired pressure in therecirculation circuit for optimal operation of the filter. In anembodiment, with a filter suitable for use in filtering plasma, the feedbooster pump and a flow restriction coil are configured to maintain arecirculation circuit pressure of between approximately 16 kPa and 26kPa (2.3 psig and 3.8 psig) and an average inlet flow rate ofapproximately 100 ml/min. Alternatively, when the system is configuredwith an ultrafilter, the feed booster pump and a flow restriction coilare configured to maintain a recirculation circuit pressure of betweenapproximately 100 kPa and 410 kPa (15 and 60 psig) and an average inletflow rate of approximately 200 ml/min.

A feed fluid recirculation pump can be included to circulate fluidthrough the feed fluid recirculation circuit that comprises a fluidconduit fluidly connecting the retentate outlet of a filter in thecircuit with the inlet of the recirculation pump. Preferably, the flowrate generated by the feed fluid recirculation pump is sufficiently highto optimize the filtering characteristics of the filter and minimize thefrequency of cleaning operations. A high flow rate may increase the fluxof fluid through the cross-flow filter membrane. A high flow rate mayalso help to prevent build-up of mineral scale deposits and biofilm,which reduce the cross-flow filter's effectiveness and lifespan. A highflow rate may also reduce damage to cells by concentrating them near thecenter of the fluid flow path and away from the walls of the conduitthrough which the fluid is flowing. In an embodiment configured with aplasma filter, the flow rate generated by the feed fluid recirculationpump can be in the range of 100-250 ml/min during fluid filtering andproduction operations. Alternatively, in a configuration with anultrafilter, the feed fluid recirculation pump can provide about 300-700ml/min during fluid filtering. The flow rate of the recirculation pumpcan be optionally lower during periods when demand for filtered fluid orpermeate is reduced or nonexistent.

Although the feed fluid recirculation pump may operate in arecirculation circuit that is maintained at a relatively high averagepressure (e.g., 400 kPa), the feed fluid recirculation pump need onlygenerate a differential pressure sufficient to overcome the pressuredrop across the feed-through side of the filter. In an embodimentwherein the filter comprises an ultrafiltration membrane, the pressuredrop through the feed side of the filter typically can be less than 172kPa (25 psi). Thus, the net power consumption of the feed pump and feedfluid recirculation pump together (feed pump—high pressuredifferential/low flow, feed fluid recirculation pump—low pressuredifferential/high flow) can be significantly less than the powerconsumption of a single-pump system that needs to generate both the highpressure and the high flow rate required for optimal operation of amembrane filter with very small pores such as an ultra filter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of a cross-flow filter with returnloop.

FIG. 2 is a conceptual model of a fluid flow network of an exemplaryfluid filtration system.

FIG. 3 is a schematic representation of a cross-flow filter linked to anadsorption filter with recirculation loop.

FIG. 4 is a schematic representation of an alternative embodiment of across-flow filter linked to an adsorption filter with recirculationloop.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The term “downstream” as used herein indicates a position in the flowpath, with respect to a current position or point of discussion, whichwill be reached in time with the normal movement of fluid through thesystem. Arrowheads along the flow path in the figures indicate thenormal direction of fluid flow. The term “upstream” may be used toindicate a position in a direction that opposes normal fluid flow, i.e.,opposes the direction of the arrowheads.

FIG. 1 shows basic elements of cross-flow filter system 601 thatcomprises a cross-flow filter 800, a return loop 120, a supply/boosterpump 600 and recirculation pump 700. The cross-flow filter system 601filters the feed fluid from the source 603, delivers the filtered fluidor permeate to port 608, while delivering concentrated feed or retentateto port 606. In other embodiments the cross-flow filter system 601 maybe part of a larger system that may have preferred operating parametersincluding but not limited to supply pressure, supply flow rates, orproduct flow rates. The product may be the retentate at port 606 or thepermeate at port 608 or fluid from both ports may be used by the largersystem.

A feed recirculation loop 120 may be used to maintain a high rate offluid flow on the feed side of the membrane of the cross-flow filter800, reducing the amount of feed fluid that otherwise would be discardedto drain. The entire recirculation loop 120 may be pressurizedsufficiently to permit filtration of fluid in the filter 800 at a raterequired by a larger system receiving the fluid product of cross-flowfilter system 601. In an embodiment in which the filter 800 is a plasmafilter, the flow rate generated by the feed fluid recirculation pump 700can be in the range of 100-250 ml/min during fluid filtering andproduction operations. Preferably, a feed booster pump 600 can boost thefeed pressure and maintain a hydrostatic pressure of betweenapproximately 16 kPa and 26 kPa (2.3 psig and 3.8 psig in the feedrecirculation loop 120. In embodiments in which the filter 800 is anultrafilter, the flow rate generated by the feed fluid recirculationpump 700 may be in the range of 300-700 ml/min during fluid filteringand production operations. In an arrangement with an ultrafilter, thebooster pump 600 may boost the feed pressure and maintain a hydrostaticpressure of between approximately 100 kPa and 410 kPa (15 and 60 psig)in the feed recirculation loop 120.

The pressurization of the recirculation loop can be accomplished, forexample, by a feed booster pump 600 combined with a flow restrictor 122and filter 800. The booster pump 600 can be provided with source fluid603 at a rate sufficient to match the amount of permeate fluid at outlet810 a and 810 b of filter 800, plus any amount of retentate flow throughflow restrictor 122 and out of the filter system via conduit 641.

In order to maintain the desired hydrostatic pressure developed by thebooster pump 600 in the recirculation loop 120, the desired permeateflow from the filter 800, and the desired fresh feed replenishment viapump 600, a flow restrictor 122 may be introduced in the flow pathbetween recirculation loop 120 and outlet port 606. This may simplycomprise a small orifice in a conduit connecting recirculation loop 120and exit port 606, a needle valve or other variable orifice valve, or arestriction coil, among other possibilities. An advantage of arestriction coil may include the possibility of reducing turbulent flowand cavitation across the restriction, thereby reducing noise andcomponent wear or erosion. A further advantage of the restriction coilis that it may provide laminar flow restriction that effectively limitsflow predictably over a wide range of pressures and flow rates. Inaddition, it may be possible to optimize the flow resistance of therestriction coil in the field by merely trimming the length of the coil.It may be advantageous to incorporate both a fixed flow restrictor suchas a restriction coil, as well as a variable valve in order to allow acontroller to control the net resistance to flow from recirculation loop120 to exit port 606. Valve 642, for example, may incorporate a variableorifice.

It may be advantageous to limit the maximum pressure in therecirculation loop 120 and the filter to prevent damage to the filterand tubing. The maximum pressure in the recirculation loop 120 may belimited, for example, by a pressure limiting valve (not shown) thatopens when the upstream pressure exceeds a pre-determined value. Thepressure limiting valve may be a back-pressure regulator that allows avariable amount of flow in order to limit the upstream pressure below apre-determined value. Alternatively the pressure limiting valve may be arelief valve that provides gradual pressure relief. Or it may be apop-safety valve that opens fully at a pre-determined pressure. The backpressure limiting valve may be built into or associated with the boosterpump 600. Alternatively the back pressure limiting valve may beinstalled in place of the flow restrictor 122 or may be plumbed inparallel to the flow restrictor 122. In an embodiment comprising aplasma filter in which there is little pressure restriction on thepermeate flow, the recirculation pressure may be limited toapproximately 25 kPa (3.6 psig) in order to protect the membrane. In anembodiment comprising an ultrafilter the recirculation pressure may belimited to approximately 410 kPa (60 psig).

Feed booster pump 600 is preferably configured to boost pressure in therecirculation loop 120, which can be achieved through the use of apositive displacement pump. Generally, this type of pump can produce adesired flow rate at a wide range of output pressures. A check valve(not shown) optionally may be positioned near the inlet of pump 600 toprevent feed fluid at high pressures from bleeding back toward thesource 603. The flow rate of the booster pump 600 may be selected toproduce the desired flow rate of permeate fluid from filter 800, plusthe flow rate of retentate via conduit 641. Knowing the desired flowrates of permeate and retentate and the desired pressure range in therecirculation loop 120, the characteristics of flow restrictor 122 maybe determined either analytically or empirically.

One example of a method to analytically determine the desiredcharacteristics of the flow restrictor 122 based on the recirculationloop pressure may be illustrated by the flow schematic shown in FIG. 2.The two pumps 600, 700 may be idealized to be constant flow sources inthe case of displacement pumps or to be constant pressure sources in thecase of centrifugal pumps. Alternatively the pump models may be derivedfrom empirical flow vs. pressure curves. In another embodiment, one orboth pump models may be treated as a pneumatically driven diaphragm pumpthat produces constant flow up to a given maximum pressure at whichpoint the flow goes to zero. The schematic in FIG. 2 includes flowresistances of the flow resistor 122, flow through the filter 804,across the membrane 802, tee fittings 627 and flow resistance of therecirculation loop 625. The flow restriction of the flow resistor R₁₂₂can be estimated by neglecting the minor resistances R₆₂₅, R₆₂₂ andusing the filter inlet pressure P, the product flow rate V₆₀₈, the flowratio of product over supply (Y=V₆₀₈/V₆₀₃), the flow ratio ofrecirculation over supply (Z=V₇₀₀/V₆₀₃) and the flow resistance throughthe filter on the feed side R₈₀₄ as:

$R_{120} = {{\frac{P_{804}}{V_{603} \cdot Y} \cdot ( \frac{1}{Y - 1} )} - {\frac{R_{804}}{2} \cdot Z \cdot {( \frac{1}{1 - Y} ).}}}$

In an embodiment, the flow resistor 122 may be a restriction coil 122.The length and the diameter of the tubing may be selected to achieve thedesired flow resistance. The diameter may be selected to assure laminarflow in a wide range of flow rates. The appropriate balance betweentubing length and diameter will depend on a number of characteristics,including the amount of space the restriction coil occupies, the cost ofmaterials, and the amount of noise it generates, among other factors.The diameter may be selected to assure laminar flow at most of thedesired flow rates. The flow resistance may be adjusted in the field,for example, by trimming the length of the restriction coil 122.

If un-replenished feed were to circulate through loop 120, its solute orparticulate concentration would progressively increase as the filter 800continued to produce purified permeate. Eventually, the solute orparticulate concentration of the recirculating feed could increase tothe point of impairing the performance of filter 800, resulting in areduction in permeate output or quality, and/or premature fouling of thefilter membrane. This may also eventually occur if feed replenishment islimited to the amount of permeate generated by the filter 800. The levelof solute or particulate concentration in the recirculating loop may bestabilized by constantly replacing a portion of the retentate (or rejectliquid) with fresh fluid via the supply pump 600. The steady state levelof solute or particulate concentration in the recirculating loop (X₆₀₆)may be estimated, for example, from the feed concentration (X₆₀₃) andthe flow ratio of product over supply (Y=V₆₀₈/V₆₀₃:

X ₆₀₆ =X ₆₀₃/(1−Y)

The constant replenishment of the recirculating loop 120 by fresh feedfluid may be achieved by having the booster pump 600 supply feed fluidat a rate above the flow rate of permeate (V₆₀₈), and allowing afraction of the retentate or reject liquid to flow through the flowrestrictor 122 to the drain line 641. The concentration of the retentatein the recirculating loop 120 may be controlled by selecting a flowrestrictor 122 with the appropriate resistance, or by otherwiseadjusting the resistance of flow restrictor 122.

Alternatively, the desired characteristics of the flow restrictor 122may be calculated based on concentrations of a particular solute orparticle and the pressure drop characteristics of the cross-flow filter800. The desired flow resistance of the flow restrictor can be estimatedin the following equation if one assumes a negligible concentration ofthe solute or particle of interest in the permeate. The flow resistanceof flow restrictor 122 may be derived from the ratio of the feedconcentration over the desired retentate concentration of a given soluteor particulate (XR=X₆₀₃/X₆₀₆), the ratio of recirculation flow oversupply flow (Z=V₇₀₀/V₆₀₃) and the flow resistances of the filter R802,R804.

$R_{120} = {{R_{802} \cdot ( \frac{1 - {XR}}{XR} )} - {\frac{R_{804}}{2} \cdot ( \frac{Z}{XR} )}}$

If the feed pump 600 is a positive displacement pump operating at afixed rate, then increasing the resistance offered by flow restrictor122 will reduce the retentate fraction and increase the production rateof permeate. However, if a lower output of permeate is desired, or ifthe solute or particulate concentration of the feed source is less thanexpected, it may be advantageous to increase the resistance to the flowof fluid from loop 120 to drain line 641, while concurrently reducingthe pumping rate of booster pump 600.

A controllable variable restriction feature can be incorporated, forexample, into valve 642. The solute or particulate content of therecirculating feed fluid may be monitored, for example, by conductivitysensor (or other types of sensors). A controller can receive the outputof sensor, and implement a pre-determined algorithm to adjust valve 642to achieve a target net flow resistance between recirculation loop 120and drain line 641, based on the trend of the recirculating feed fluidconductivity. The controller may vary the flow resistance of the valve642 to maintain a desired level of solute or particulate concentrationin the recirculation loop 120 as measured by the conductivity or othertype of sensor.

A fluid recirculation pump 700, positioned within the recirculation loop120, can boost the fluid flow velocity along the filter membranesufficiently to improve the filter performance. Typically higher fluidflow rates of along the filter membrane produce higher flux of permeate.Alternatively, higher flow rates in the recirculation loop 120 may allowthe booster pump 600 to be operated at a lower pressure for any givenflow rate of permeate. In addition, a higher flow rate in therecirculation loop 120 may allow for the use of a filter having asmaller filter area.

Higher fluid flow rates may provide different benefits with differenttypes of cross-flow filter membranes. For example, higher blood flowrates past microfiltration membranes may reduce damage to cells andreduce fouling of the membrane surface. One possible explanation forthis effect is that higher laminar flow rates may increase the liftingforce on cells, pulling them to the center of the flow path and awayfrom the membrane surface or conduit walls. This transport mechanism isoften termed inertial lift. Microfiltration of fluid containing cells orcellular elements may benefit from a recirculation pump that produces asteady flow of fluid. Periodic flow from, for example a singleperistaltic pump, could create mixing in the flow paths and breakdownthe laminar flow that tends to keep cells away from the filter walls.Rather, an axial pump may allow laminar flow to develop that tends toconcentrate the cells away from the membrane surface. Other alternativesfor generating steady flow include the use of dual linear peristalticpumps, dual diaphragm pumps, vane pumps or radial centrifugal pumps.High fluid flow rates may also inhibit adhesion of dissolved orsuspended compounds (such as proteins or other macromolecules) to thefilter membrane, and thus help to maintain the filtering efficiency ofthe membrane.

In some cases, turbulent fluid flow across a filter membrane may bepreferred. Ultrafiltration and nanofiltration membranes exposed to highfluid flow rates may be used in conjunction with structures (e.g.,separators) to increase the mixing of the fluid flowing past themembrane. Increased mixing of the feed fluid in this case may increasethe concentration of the permeable elements and compounds at themembrane surface of the filter. The increased flow rate and mixing mayalso inhibit biofouling or scaling of the membrane surface. Withoutbeing bound to a single theory, one possible explanation for reducedfouling at high flow rates is that the fast turbulent flow of fluid overthe surface of the membrane creates high shear stress at the membranesurface which agitates or abrades biofilms and other fouling materialsthat may collect on the membrane surface.

Regardless of the net flow of into and out of the recirculation loop120, the recirculation pump 700 can boost the flow rate of fluidcirculating through the filter 800 via inlet 830 and discharge outlet820. Thus the booster pump 600, while operating at a relatively highpressure differential, can do so at a relatively low flow rate, whilethe high-flow recirculation pump 700, while operating at a relativelyhigh flow rate, can do so at a relatively low pressure differential.Separating the pressure-boosting function to operate the filter 800 fromthe flow-boosting function to maintain a high rate of flow across filter800 may result in a reduction of net power consumption by the one ormore pump motors in the cross-flow filter system 601.

The cross-flow filter 800 may be a commercially available filter modulecontaining a membrane that retains a given type or size of cells,cellular elements, particles or solutes in the retentate, while allowingsmaller particles or compounds along with the liquid to past through themembrane to form the permeate. The cross-flow filter membrane may becharacterized by the size of particles that are retained in the feedfluid. One example is a microfiltration membrane used to separate intactcells from the rest of the components in the feed fluid. The Prismaflex®System marketed by Gambro Lundia AB, for example, includes a plasmafilter (a microfiltration filter) that separates the red blood cellsfrom the plasma. The pores in the microfiltration membrane typicallyhave a size in the range of 0.05 to 1 mm. Ultrafiltration membranes arefiner than microfiltration membranes and typically have pore sizes inthe range of 10 kiloDaltons up to 500 kiloDaltons. An ultrafiltrationmembrane may be used to separate proteins from salts, viruses or otherproteins. The tightest membranes used in nanofiltration or reverseosmosis separate solutes such as salts and other small molecules withmolecular masses less than 1.5 kiloDaltons from water or other solvents.

The filter membrane in the cross-flow filter 800 may be held in any of anumber of different modules. Hollow fibers modules are comprised of abundle of thin fibers in a shell with a manifold at each end todistribute the feed fluid to the center of the many fibers and isolatethe feed fluid from the permeate fluid in the shell. The hollow fiberstypically have open inner diameters in the range of 0.1 to 2.0 mm. Thefeed fluid flows through the center of a fiber and the permeate flowsthrough the walls of the fiber to the shell side of the filter module.Hollow fibers are typically used with shear sensitive materials such ablood due to the low shear rates in the fiber centers. Flat plate andspiral wound modules are comprised of layers of membrane with channelsconnected to the feed manifold, alternating with other channelsconnected to permeate ports. Separators may be placed in the feedchannels to promote turbulent mixing and higher flux of permeablecompounds across the membrane. However, separators may increase the fluxacross the membrane at the expense of higher pumping power and possibledamage to intact cells when the feed fluid is a composition of bloodelements.

In an embodiment, a pressurized reservoir or vessel (not shown) may beincorporated into the recirculation loop that supplies fluid to thefilter. The pressurized reservoir can connected to the loop via a teefitting or may be in-line with the recirculation flow circuit. Thereservoir may be preferentially placed downstream of the filter 800 andupstream of the recirculation pump 700.

A controller (not shown) may monitor the pressure transducer 660 andcontrol the pressure in the recirculation loop by varying the pumps 600,700 upstream of the filter or the flow control devices downstream of thefilter. In one example the controller may vary the speed of the supplypump 600 and/or recirculation pump 700 to maintain the measured pressureat 660 within pre-determined limits. In another example the controllermay vary the valves 642, 644 on the retentate and permeate lines 641,643 to maintain the measured pressure at 660 within pre-determinedlimits. In another example, the controller may control the pressure isthe recirculation loop by controlling the flows through the retentateand permeate lines 641, 643 by pumps such as pump 646 on the permeateline.

Referring to FIG. 1, the pressure in the recirculation loop may becontrolled with a pressure switch 660 that enables/disables the pumps600, 700. In one embodiment the pressure switch disables the boosterpump 600 if the pressure exceeds a given value. The pressure switch 660may re-enable booster pump once the pressure drops a given amount belowthe set pressure. Alternatively, the pressure switch 660 may disable thebooster pump 600 and the recirculation pump 700 if the pressure exceedsa pre-determined value. The pressure switch 660 may re-enable thebooster pump 600 and the recirculation pump 700 once the pressure dropsa given amount below the set pressure.

An alternative embodiment of the cross-flow filter system 601 mayinclude a permeate valve 644 on line 643 to control the flow of permeatethrough the filter membrane. The permeate valve 644 may for example beclosed after the system 601 is primed to allow the feed fluid tocirculate through filter 800 without permeating through the membrane.This may be useful, for example, with the microfiltration of blood.Prior to filtering operations, it may be beneficial to allow the bloodto flow through the filter without permeating across the filter membranein order to improve the hemo-compatibility of the filter components andto reduce membrane fouling. In another implementation, the permeatevalve 644 may be closed to facilitate backflushing of the filtermembrane as the feed flow past the membrane creates a reversed pressuregradient across the membrane.

In another embodiment, the cross-flow filter system 601 may include athird pump 646 along the permeate fluid conduit 643. The permeate pump646 may be used to control the rate of permeate flow in conduit 643. Theconcentration of the retained material in the recirculation loop mayalso be controlled by the combined action of the pumps 646, 600 and theflow restrictor 122. Additionally, the permeate pump 646 may be areversible flow pump, so that it may flow permeate back through themembrane into the cross-flow filter retentate stream. The permeate pump646 may be used to backflush the filter membrane periodically. A reverseflow through the filter may dislodge particles, scale and biofilm thataggregate on the surface of the filter core. The back-flushing proceduremay require a separate reservoir of permeate-compatible fluid to be usedas the backflushing fluid. For example, in a blood-processing system, acontainer of plasma may be used, either vented for sterile air ingress,or constructed of a non-vented collapsible bag.

In the following discussion, reference will be made to an exemplaryembodiment comprising a blood treatment system in which plasma isseparated from blood using a cross-flow plasma filter, following whichthe plasma may then be treated by removal of particular biologicalmaterials or chemical compounds through an appropriately selectedadsorption filter. It should be noted, however, that the invention isnot limited to the filtering of blood and plasma, or even of otherbiological fluids (such as, e.g., dialysate solution). The invention maybe applied to any liquid containing dissolved or suspended solutes orparticles for which cross-flow filtration followed by adsorptionfiltration would be useful. In blood treatments systems, it should benoted that a biological fluid other than plasma may be extracted fromblood depending on the type of cross-flow filter selected. Thesubsequent passage of this fluid through an adsorption filter, and therecirculation features of the invention will apply equally well to thistype of fluid.

In one embodiment a fluid treatment module 1000 may incorporate a firstreturn loop that returns the retentate of the membrane filter exit tothe inlet of the membrane filter and incorporates a second return loopthat returns the permeate to the inlet of the membrane filter as shownin FIG. 3. In applications in which plasma is separated from whole bloodin the membrane filter, returning the plasma to the membrane filterintake maintains the blood hematocrit at more physiologic levels toreduce problems such as, for example, clumping, clotting or hemolysis inthe membrane filter. In FIG. 3, the permeate (or, e.g., separatedplasma) is further filtered by an adsorption filter 1200 to remove aparticular contaminant, which may include (and is not limited to) one ormore of the following: toxins, particulates, cytokines, viruses, andbiological or chemical contaminants. The flow through the return loop1120 is much higher than the flow of fluid (e.g., blood) into and out ofthe treatment module 1000 through the input and output lines 1350, 1355.A fraction of the fluid or plasma entering cross-flow filter 1800 ispulled across the filter media by permeate pump 1646 and then flowedthrough and treated by the absorption filter 1200. The treated permeatemay then be returned to the incoming feed line 1365, where it mixes withthe incoming fluid (such as, e.g., whole blood in an extracorporealtreatment system). This mixture of source fluid or whole blood andtreated permeate or plasma then mixes with the recirculating fluid orblood mixture from line 1120 before reentering filter 1800. The ratio offlow through the return loop 1120 relative to the intake flow in 1350and the ratio of permeate or plasma flow in the permeate line 1360relative to the intake flow in line 1350 may be selected so that most ofthe permeate or plasma flows through the adsorption filter 1200 manytimes before exiting the fluid treatment module 1000. The multiplepassages through the adsorption filter 1200 allow the fluid treatmentmodule 1000 to reduce the concentration of contaminants to any desiredlevel and well below what could be achieved in a single pass through theadsorption filter 1200. The fluid treatment module 1000 can be operatedto produce a specified level of decontamination by selecting theappropriate ratios of recirculation and permeate flow relative to theinlet flow into the fluid treatment module and knowing thepre-determined rate of adsorption or filtering in the adsorption filter1200 for the given contaminant.

In an extracoporreal treatment system, the fluid treatment module 1000may be connected to a patient's blood supply via access line 1350.Processed blood is returned via line 1355.

A controller (not shown) may provide power to and/or may control thespeed of the pumps 1600, 1646, 1700, and control the operation ofvarious valves in the system. The controller may also monitor signalsfrom one or more pressure sensors 1305, 1310, 1318, 1322. The controllermay also monitor the signals from temperature sensors, conductivitysensors and/or oxygen concentration sensors. The supply pump 1600 pullsthe blood into the fluid treatment module 1000 and returns it to thepatient. The supply pump 1600 may be controlled to provide a specificrate of flow through the fluid treatment module 1000. Alternatively, thesupply pump 1600 may be controlled to provide a desired pressure asmeasured by the feed pressure sensor 1310. In addition, the supply pump1600 may be controlled to limit any negative pressure created in theaccess line 1350 as measured by the access pressure sensor 1305. Thetreated permeate or plasma from the adsorption filter 1200 may enter thefeed line 1365 and mix with the fluid entering the system (e.g., wholeblood) from the supply pump 1600.

In some examples, a chemical or medication (such as heparin) may beinfused in the feed line 1365 from a pump 1370. The medication pump 1370may be any assembly suitable to deliver a controllable amount ofmedication based on the flow rate of the source fluid (e.g., wholeblood) through the supply pump 1600. The medication pump 1370 may beselected from known pump technologies including but not limited tosyringe pumps, rotary peristaltic pumps, linear peristaltic pumps,pneumatically controlled diaphragm pumps. In an extracorporeal system,heparin is a well known anti-coagulant that is typically added to reduceclotting and agglomeration of blood. A chemical or medication may beadded at a rate that is specified fraction of the incoming source fluid,such as whole blood. The controller (not shown) may control the flowrate of the medication pump 1370 based on a signal indicative of thesource fluid flow rate. The source fluid (e.g., blood) flow rate signalmay be the speed of the supply pump 1600 or may be calculated from oneor both pressures measured by sensors 1305, 1310.

The mixture of treated permeate and source fluid may then mix with therecirculating fluid from return line 1120 before entering the cross-flowfilter 1800. In the case of an extracorporeal blood treatment system,the mixture of treated plasma and whole blood mixes with therecirculating blood mixture from the return line 1120 before enteringthe plasma filter 1800. A fraction of the fluid entering filter 1800flows across the filter medium to enter the permeate line 1360. The flowacross the filter medium is controlled in part by the permeate pump 1646which may create a pressure difference across the filter medium thatdrives the flow of permeate. The controller (not shown) may vary thepermeate pump 1646 to achieve a desired pressure in the permeate line1360 as measured by the permeate pressure sensor 1318. Alternatively,the permeate pump 1646 may controlled to achieve a desired pressuredifference across filter 1800 as measured by the difference of thearterial and permeate pressure sensors 1310, 1318.

In extracorporeal blood treatment systems, a hemoglobin detector 1210may be placed in the permeate line 1360 to detect failure in the plasmafilter 1800. The hemoglobin detector 1210 would react to either wholeblood cells or the components of red blood cells. Whole red bloods mayenter the plasma line 1360 if the filter media has a tear or breakallowing whole blood to enter the plasma line 1360. Red blood cellcomponents may enter the plasma line 1360, due to hemolysis in thefilter or recirculation pump. Hemolysis or red blood cell destructionmay occur in the plasma filter if red blood cells plate out on thesurface or are sheared apart near the surface of the filter media. Thecontroller may monitor the signal from the hemoglobin detector. Thecontroller may issue a warning if the signal of the hemoglobin detectorexceeds a given level but is less than a second higher level. Thecontroller may further vary the speed the return pump or the plasma pumpin response to the detection of a low level of hemoglobin. Thecontroller may issue an alarm if the hemoglobin detector signal exceedsa second pre-determined threshold. The controller may also initiate ashut-down of the treatment module 1000, when it issues an alarm due tothe presence of a pre-determined level of hemoglobin in the plasma line1360.

The Adsorption filter 1200 may be any permeate treatment device thatremoves contaminants from the permeate flowing through it. Adsorptionfilter 1200 may include (but not be limited to) a charcoal or activatedcarbon adsorption column. Other examples may include leptin adsorptionfilters such as the Aethlon Hemopurifier® made by Aethlon Medical Inc.,endotoxin filters such as the PMX-20R® made by Toray Industries, Inc.and cytokine extractors such as the CytoSorb® system made byCytoSorbents, Inc. These elements may adsorb pathogens in the permeatenon-selectively such as a charcoal or may be designed to selectivelyadsorb a particular pathogen or toxin. The adsorbed elements remain inthe adsorption filter 1200, while the treated permeate exits beforemixing with the incoming source fluid (such as whole blood).

The permeate line may include a variable volume chamber 1220 (which may,for example, comprise a collapsible chamber having compliant walls) tofacilitate backflushing the filter 1800. The backflushing may beaccomplished during operation of the treatment module 1000 by closingthe backflush clamp 1230 and allowing the variable volume chamber 1220to fill with pressurized liquid. Then the permeate pump 1646 may bedriven backward to push permeate back across the filter medium.Backflushing the filter 1800 may help to dislodge particles and cellularelements that may clog the filter medium.

The fluid that flows through the filter 1800 and not across the filtermedium exits the filter as the retentate. In an extracorporeal treatmentsystem, most of this mixture of red blood cells and plasma isrecirculated to the inlet of the plasma filter by the return pump 1700.The return pump 1700 may produce a flow rate in the return line 1120that is higher than the inlet 1365 flow rate. In some embodiments, thereturn line flow rate can range up to about twice as high as the inletflow rate. In other embodiments the return line flow rate can be higherthan twice the inlet flow rate. The controller (not shown) may controlthe speed of the return pump 1700 to maintain a given ratio of the speedof the supply pump 1600. Alternatively, the return pump 1700 may becontrolled based on the characteristics of filter 1800. In addition, thereturn pump 1700 may be controlled based on the desired therapy, whichdetermines the type of filter and adsorption filter chosen, and thedesired rate of contaminant removal.

A small fraction of the retentate exiting the filter 1800 will flowtoward the exit of the treatment module 1000 via line 1355. In anextracorporeal blood treatment system, protamine may be infused into theexiting line 1355 to reverse any administered heparin. The exit line1355 may include elements to protect a patient from air entering theirblood stream. The first element may be an air trap 1330 to trap gasesthat may evolve from the blood or that may otherwise enter the fluidflow paths of the treatment system. The air trap 1330 may be, forexample, a ‘run-full’ air trap similar to that disclosed in US PatentApplication Publication no. 2009/0114582. The second element may be anAir-In-Line (AIL) detector 1340 that detects the presence of gas bubblesor foam in the blood exiting the treatment module 1000. The controllermay monitor the AIL signal and issue a warning if the detected gas levelexceeds a first threshold and remains less than a second threshold. Ifthe AIL signal exceeds the second threshold, the controller may signalan alarm and stop the flow of blood by turning off at least the supplypump 1600 and closing outlet clamp 1345.

Another embodiment of a Treatment Module 1100 is shown in FIG. 4 and isreferred herein as the post dilution treatment module. Similar to thetreatment module 1000, the post-dilution treatment module 1100 includesa supply pump 1600 to control the flow of source fluid (such as blood)into the system, a return pump 1700 to recirculate retentate from themembrane filter 1800 to the filter inlet and a permeate pump 1646 tocontrol the flow of permeate through the filter material. Similar to thetreatment module 1000, the post-dilution treatment module 1100 mayrecirculate the retentate so that the flow rate through the cross-flowmembrane filter is high enough to reduce fouling of the filter surface.The supply pump 1600 and return pump 1700 may be controlled as describedabove. The use of a medication pump 1370, a sensor such as a hemoglobinsensor 1210, air trap 1330, AIL sensor 1340 and valve 1345 are the sameas described in the treatment module 1000 description.

The controller (not shown) may vary the speed of the permeate pump 1646to achieve the desired flowrate across the cross-flow filter media andprovide enough pressure to deliver the flow to either the feed line 1365or the outflow line 1355. The controller may also vary the speed of thepermeate pump 1646 to achieve a desired pressure difference or limit thepressure difference across the cross-flow filter media. The speed of thepermeate pump 1646 may be selected by the controller based on one ormore from the following pressure sensors feed pressure sensor 1310,permeate pressure sensor 1318, and the permeate outlet pressure sensor1312.

The post-adsorption treatment module 1100 allows the treated permeate tobe directed to either the feed line 1365 or the outlet line 1355. If theadsorption filter 1200 is particularly efficient, the desired level ofcontamination reduction may be achieved by a single pass of permeatethrough it. In that case, it may be preferable to limit the number ofrepeated transits of treated permeate across the cross-flow filter 1800and adsorption filter 1200. In this case the 3-way valve 1240 at theexit of the adsorption filter 1200 may be commanded by the controller(not seen) to direct the treated permeate toward the outlet line 1355.

The post-dilution treatment module 1100 may include a sensor (such as,e.g., a conductivity sensor or hematocrit sensor) 1235 upstream of themembrane filter inlet to signal the controller (not shown) if the soluteconcentration of the recirculating fluid, (or the hematocritconcentration in an extracorporeal treatment system) exceeds a thresholdvalue. Excessively concentrated fluid may foul the membrane filter 1800.In an extracorporeal treatment system, an excessively high hematocritmay cause increased hemolysis or more rapid clogging of the membrane offilter 1800. The controller (not shown) may respond to excessive soluteor particulate concentration levels by directing the 3-way valve 1240 toa position in which more of the treated permeate is sent to the feedline 1365 via line 1363. The returned permeate will reduce theconcentration of the recirculating fluid. The 3-way valve may also beadjusted by switching between the two positions or by being held in anintermediate position that will direct some but not all of the treatedpermeate to the fill line 1365. Proportional control of valve 1240 mayallow control the solute or particulate concentration of therecirculating fluid to a desired or pre-determined level.

What is claimed is: 1.-19. (canceled)
 20. A fluid filtration systemcomprising: a crossflow filter having a filter inlet, a retentateoutlet, and one or more permeate outlets configured to provide a firststage filtration, the retentate outlet connected to the filter inlet viaa first controllable pump and forming a recirculation path; the one ormore permeate outlets of the crossflow filter connected to an adsorptionfilter inlet of an adsorption filter providing a second stagefiltration, an adsorption filter outlet of the adsorption filterconnected to the recirculation path and a filtration system outlet via acontrollable valve; and a controller arranged to control the first pumpand the valve; wherein the controller is configured to control the valveto direct at least a portion of an output flow of the adsorption filterto the recirculation path during operation of the filtration system. 21.The system of claim 20, further comprising a second controllable pumpinterposed between the one or more permeate outlets and the adsorptionfilter inlet, wherein the controller is configured to control the secondpump to regulate flow into the adsorption filter.
 22. The system ofclaim 21, further comprising a third controllable pump connected to afiltration system inlet, wherein the controller is configured to controlthe third pump to regulate fluid flow from an external source into therecirculation path.
 23. The system of claim 22, wherein the controlleris arranged to control the third pump and the valve to balance fluidflow leaving the filtration system through the filtration system outletwith fluid flow entering the filtration system through the filtrationsystem inlet.
 24. The system of claim 21, further comprising a firstpressure sensor associated with the crossflow filter inlet, a secondpressure sensor associated with the one or more permeate outlets,wherein the controller is arranged to receive pressure data from thefirst and second pressure sensors, and to control the first or secondpump based on the pressure data.
 25. The system of claim 24, furthercomprising a third pressure sensor associated with the adsorption filteroutlet, wherein the controller is arranged to receive pressure data fromthe third pressure sensor, and to control the second pump based on thepressure data from the first, second or third pressure sensors.
 26. Thesystem of claim 22, further comprising an inlet pressure sensorassociated with the filtration system inlet, wherein the controller isarranged to control the third pump based on pressure data received fromthe inlet pressure sensor.
 27. The system of claim 20, furthercomprising a conductivity sensor or hematocrit sensor arranged to detecta conductivity or a hematocrit concentration of a fluid entering thecrossflow filter, wherein the controller is arranged to control thevalve to adjust a proportion of fluid flow from the adsorption filterdirected to the recirculation path.
 28. The system of claim 27, whereinthe controller is arranged to control the valve to adjust the proportionof fluid flow directed to the recirculation path to maintain theconductivity or hematocrit concentration of the fluid within apre-determined range.
 29. The system of claim 20, further comprising ahemoglobin detector configured to detect red blood cells or componentsof red blood cells in the one or more permeate outlets of the crossflowfilter, wherein the controller is arranged to issue a user alert if asignal from the hemoglobin detector indicates a predetermined level ofred blood cells or components of red blood cells.
 30. A blood filtrationsystem comprising: a crossflow filter having a filter inlet for blood, aretentate outlet, and one or more permeate outlets for plasma configuredto provide a first stage filtration of the blood, the retentate outletconnected to the filter inlet via a first controllable pump and forminga recirculation path; the one or more permeate outlets of the crossflowfilter carrying the plasma to an adsorption filter inlet of anadsorption filter providing a second stage filtration of the plasma, anadsorption filter outlet of the adsorption filter connected to therecirculation path and a filtration system outlet via a controllablevalve; and a controller arranged to control the first pump and thevalve; wherein the controller is configured to control the valve todirect at least a portion of plasma flow from the adsorption filter tothe recirculation path to recombine with the blood during operation ofthe filtration system.
 31. The system of claim 30, further comprising asecond controllable pump interposed between the one or more permeateoutlets and the adsorption filter inlet, wherein the controller isconfigured to control the second pump to regulate plasma flow into theadsorption filter.
 32. The system of claim 31, further comprising athird controllable pump connected to a filtration system inlet, whereinthe controller is configured to control the third pump to regulate bloodflow from an external source into the recirculation path.
 33. The systemof claim 32, wherein the controller is arranged to control the thirdpump and the valve to balance fluid flow leaving the filtration systemthrough the filtration system outlet with fluid flow entering thefiltration system through the filtration system inlet.
 34. The system ofclaim 31, further comprising a first pressure sensor associated with thecrossflow filter inlet, a second pressure sensor associated with the oneor more permeate outlets, wherein the controller is arranged to receivepressure data from the first and second pressure sensors, and to controlthe first or second pumps based on the pressure data.
 35. The system ofclaim 34, further comprising a third pressure sensor associated with theadsorption filter outlet, wherein the controller is arranged to receivepressure data from the third pressure sensor, and to control the secondpump based on the pressure data from the first, second or third pressuresensors.
 36. The system of claim 35, further comprising a fourthpressure sensor associated with the filtration system inlet, wherein thecontroller is arranged to control the third pump based on pressure datareceived from the fourth pressure sensor.
 37. The system of claim 30,further comprising a conductivity sensor or hematocrit sensor arrangedto detect a conductivity or a hematocrit concentration of the bloodentering the crossflow filter, wherein the controller is arranged tocontrol the valve to adjust a proportion of plasma flow from theadsorption filter directed to the recirculation path.
 38. The system ofclaim 37, wherein the controller is arranged control the valve to adjustthe proportion of plasma flow directed to the recirculation path tomaintain the conductivity or hematocrit concentration of the bloodwithin a pre-determined range.
 39. The system of claim 30, furthercomprising a hemoglobin detector configured to detect red blood cells orcomponents of red blood cells in the one or more permeate outlets of thecrossflow filter, wherein the controller is arranged to issue a useralert if a signal from the hemoglobin detector indicates a predeterminedlevel of red blood cells or components of red blood cells.
 40. Thesystem of claim 30 wherein the adsorption filter is arranged to at leastpartially remove toxins, particulates, cytokines, viruses, or biologicalor chemical contaminants from the plasma.
 41. A method of performingtwo-stage filtering of fluid of a filtration system comprising:controlling a first pump to recirculate a fluid in a recirculation pathfrom a retentate outlet of a crossflow filter to an inlet of thecrossflow filter; controlling a second pump to pass a permeate of thecross-flow filtered fluid through an adsorption filter; and controllinga valve connected to an adsorption filter outlet to direct at least aportion of the adsorption-filtered permeate to the recirculation path,and a remaining portion of the adsorption-filtered permeate to an outletof the filtration system.
 42. The method of claim 41, furthercomprising: controlling a third pump to regulate an amount of the fluidentering the filtration system from an outside source.
 43. The method ofclaim 42, further comprising: controlling the third pump and the valveto balance a flow of the fluid entering the filtration system with aflow of the filtered permeate leaving the filtration system through anoutlet of the filtration system.
 44. The method of claim 42, furthercomprising: receiving pressure data from a first pressure sensorassociated with an inlet of the crossflow filter, a second pressuresensor associated with a permeate outlet of the crossflow filter; andcontrolling the first or second pump based on the pressure data.
 45. Themethod of claim 44, further comprising: receiving pressure data from athird pressure sensor associated with the adsorption filter outlet; andcontrolling the second pump based on the pressure data from the first,second or third pressure sensors.
 46. The method of claim 45, furthercomprising: Receiving pressure data from a fourth pressure sensorassociated with the filtration system inlet; and controlling the thirdpump based on pressure data received from the fourth pressure sensor.47. The method of claim 41, further comprising: receiving data from aconductivity sensor arranged to detect a conductivity of the fluid inthe recirculation path, or data from a hematocrit sensor arranged todetect a hematocrit level of the fluid in the recirculation path; andcontrolling the valve to adjust a proportion of filtered permeate flowfrom the adsorption filter directed to the recirculation path.
 48. Themethod of claim 47, further comprising: controlling the valve to adjustthe proportion of filtered permeate flow directed to the recirculationpath to maintain the conductivity or hematocrit concentration of thefluid in the recirculation path within a pre-determined range.
 49. Themethod of claim 41, further comprising: using the adsorption filter toat least partially remove toxins, particulates, cytokines, viruses, orbiological or chemical contaminants from the permeate.